Albumin-bound paclitaxel plus anlotinib in patients with recurrent, platinum-resistant primary epithelial ovarian cancer (A-Plus): a phase II, single-arm, prospective study

Abstract

This study aimed to evaluate the efficacy and safety of combining albumin-bound paclitaxel (ab-paclitaxel) and anlotinib for ovarian cancer. In this study, 44 patients diagnosed with platinum-resistant ovarian cancer were enrolled. Patients received ab-paclitaxel along with anlotinib until disease progression or intolerable toxicity. Efficacy was assessed according to RECIST 1.1 criteria or Rustin’s criteria. The primary endpoint was the investigator-evaluated objective response rate (ORR). 44 patients were enrolled between January 2021 and March 2023 with a median age of 49 years. Twenty-nine had measurable lesions and 15 had non-measurable lesions. Overall, the investigator-evaluated ORR was 56.8% (25/44; 95% CI 0.411–0.713) in intention-to-treat population and 58.1% (25/43; 95% CI 0.422–0.726) in per-protocol population. The median progression-free survival was 9.8 months, and the median duration of response was 7.4 months. For safety, grade 3/4 adverse events (AEs) included leukopenia, gum pain, hypertension, and hand-foot syndrome. The response rates were 55.0% (11/20) in patients with previous use of antiangiogenic reagents and who had previous use of PARP inhibitors. The combination of ab-paclitaxel and anlotinib showed promising anti-tumor activity and a manageable safety profile in platinum-resistant ovarian cancer. Patients with previous use of antiangiogenic drugs or PARP inhibitors still benefited from this protocol.

Keywords

anlotinib / ab-paclitaxel / efficacy / safety

References

[1] Sung H , Ferlay J , Siegel RL , Laversanne M , Soerjomataram I , Jemal A , Bray F . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71(3): 209–249

[2] Xia C , Dong X , Li H , Cao M , Sun D , He S , Yang F , Yan X , Zhang S , Li N , Chen W . Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl) 2022; 135(5): 584–590

[3] Sambasivan S . Epithelial ovarian cancer: review article. Cancer Treat Res Commun 2022; 33: 100629

[4] Buechel M , Herzog TJ , Westin SN , Coleman RL , Monk BJ , Moore KN . Treatment of patients with recurrent epithelial ovarian cancer for whom platinum is still an option. Ann Oncol 2019; 30(5): 721–732

[5] Muggia FM , Hainsworth JD , Jeffers S , Miller P , Groshen S , Tan M , Roman L , Uziely B , Muderspach L , Garcia A , Burnett A , Greco FA , Morrow CP , Paradiso LJ , Liang LJ . Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997; 15(3): 987–993

[6] Sehouli J , Stengel D , Harter P , Kurzeder C , Belau A , Bogenrieder T , Markmann S , Mahner S , Mueller L , Lorenz R , Nugent A , Wilke J , Kuznik A , Doering G , Wischnik A , Sommer H , Meerpohl HG , Schroeder W , Lichtenegger W , Oskay-Oezcelik G . Topotecan weekly versus conventional 5-day schedule in patients with platinum-resistant ovarian cancer: a randomized multicenter Phase II trial of the North-Eastern German Society of Gynecological Oncology Ovarian Cancer Study Group. J Clin Oncol 2011; 29(2): 242–248

[7] Rose PG , Blessing JA , Mayer AR , Homesley HD . Prolonged oral etoposide as second-line therapy for platinum-resistant and platinum-sensitive ovarian carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 1998; 16(2): 405–410

[8] Markman M , Webster K , Zanotti K , Kulp B , Peterson G , Belinson J . Phase 2 trial of single-agent gemcitabine in platinum-paclitaxel refractory ovarian cancer. Gynecol Oncol 2003; 90(3): 593–596

[9] Rose PG , Blessing JA , Ball HG , Hoffman J , Warshal D , DeGeest K , Moore DH . A phase II study of docetaxel in paclitaxel-resistant ovarian and peritoneal carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2003; 88(2): 130–135

[10] An D , Banerjee S , Lee JM . Recent advancements of antiangiogenic combination therapies in ovarian cancer. Cancer Treat Rev 2021; 98: 102224

[11] Shaw D , Clamp A , Jayson GC . Angiogenesis as a target for the treatment of ovarian cancer. Curr Opin Oncol 2013; 25(5): 558–565

[12] Duska LR , Java JJ , Cohn DE , Burger RA . Risk factors for readmission in patients with ovarian, fallopian tube, and primary peritoneal carcinoma who are receiving front-line chemotherapy on a clinical trial (GOG 218): an NRG oncology/gynecologic oncology group study (ADS-1236). Gynecol Oncol 2015; 139(2): 221–227

[13] Oza AM , Cook AD , Pfisterer J , Embleton A , Ledermann JA , Pujade-Lauraine E , Kristensen G , Carey MS , Beale P , Cervantes A , Park-Simon TW , Rustin G , Joly F , Mirza MR , Plante M , Quinn M , Poveda A , Jayson GC , Stark D , Swart AM , Farrelly L , Kaplan R , Parmar MK , Perren TJ; ICON7 trial investigators . Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol 2015; 16(8): 928–936

[14] Pujade-Lauraine E , Hilpert F , Weber B , Reuss A , Poveda A , Kristensen G , Sorio R , Vergote I , Witteveen P , Bamias A , Pereira D , Wimberger P , Oaknin A , Mirza MR , Follana P , Bollag D , Ray-Coquard I . Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol 2014; 32(13): 1302–1308

[15] Zhu Y , Wang X , Chen Z , Zhou L , Di X , Fan P , He Z . Anlotinib suppressed ovarian cancer progression via inducing G2/M phase arrest and apoptosis. J Clin Med 2022; 12(1): 162

[16] Liu G , Feng Y , Li J , Deng T , Yin A , Yan L , Zheng M , Xiong Y , Li J , Huang Y , Zhang C , Huang H , Wan T , Huang Q , Lin A , Jiang J , Kong B , Liu J . A novel combination of niraparib and anlotinib in platinum-resistant ovarian cancer: efficacy and safety results from the phase II, multi-center ANNIE study. EClinicalMedicine 2022; 54: 101767

[17] Lan CY , Zhao J , Yang F , Xiong Y , Li R , Huang Y , Wang J , Liu C , Bi XH , Jin HH , Meng J , Zhao WH , Zhang L , Wang YF , Zheng M , Huang X . Anlotinib combined with TQB2450 in patients with platinum-resistant or -refractory ovarian cancer: a multi-center, single-arm, phase 1b trial. Cell Rep Med 2022; 3(7): 100689

[18] Shen W , Jing C , Tian W , Zhang W , Ren Y , Shan B , Wang H . Anlotinib in patients with recurrent platinum resistant/refractory ovarian cancer: a prospective, single arm, phase II study. Int J Gynecol Cancer 2023; 33(11): 1764–1770

[19] Tillmanns TD , Lowe MP , Walker MS , Stepanski EJ , Schwartzberg LS . Phase II clinical trial of bevacizumab with albumin-bound paclitaxel in patients with recurrent, platinum-resistant primary epithelial ovarian or primary peritoneal carcinoma. Gynecol Oncol 2013; 128(2): 221–228

[20] Herzog TJ , Vermorken JB , Pujade-Lauraine E , Provencher DM , Jagiello-Gruszfeld A , Kong B , Boman K , Park YC , Parekh T , Lebedinsky C , Gómez J , Monk BJ . Correlation between CA-125 serum level and response by RECIST in a phase III recurrent ovarian cancer study. Gynecol Oncol 2011; 122(2): 350–355

[21] Rustin GJ , Vergote I , Eisenhauer E , Pujade-Lauraine E , Quinn M , Thigpen T , du Bois A , Kristensen G , Jakobsen A , Sagae S , Greven K , Parmar M , Friedlander M , Cervantes A , Vermorken J; Gynecological Cancer Intergroup . Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer 2011; 21(2): 419–423

[22] Rustin GJ , Nelstrop AE , McClean P , Brady MF , McGuire WP , Hoskins WJ , Mitchell H , Lambert HE . Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 1996; 14(5): 1545–1551

[23] Rustin GJ , Nelstrop AE , Tuxen MK , Lambert HE . Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 1996; 7(4): 361–364

[24] Rustin GJ , Nelstrop AE , Bentzen SM , Piccart MJ , Bertelsen K . Use of tumour markers in monitoring the course of ovarian cancer. Ann Oncol 1999; 10(Suppl 1): S21–S27

[25] Rustin GJ , Nelstrop AE , Bentzen SM , Bond SJ , McClean P . Selection of active drugs for ovarian cancer based on CA-125 and standard response rates in phase II trials. J Clin Oncol 2000; 18(8): 1733–1739

[26] Teneriello MG , Tseng PC , Crozier M , Encarnacion C , Hancock K , Messing MJ , Boehm KA , Williams A , Asmar L . Phase II evaluation of nanoparticle albumin-bound paclitaxel in platinum-sensitive patients with recurrent ovarian, peritoneal, or fallopian tube cancer. J Clin Oncol 2009; 27(9): 1426–1431

[27] Coleman RL , Brady WE , McMeekin DS , Rose PG , Soper JT , Lentz SS , Hoffman JS , Shahin MS . A phase II evaluation of nanoparticle, albumin-bound (nab) paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol Oncol 2011; 122(1): 111–115

[28] Baumann KH , du Bois A , Meier W , Rau J , Wimberger P , Sehouli J , Kurzeder C , Hilpert F , Hasenburg A , Canzler U , Hanker LC , Hillemanns P , Richter B , Wollschlaeger K , Dewitz T , Bauerschlag D , Wagner U . A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy. Ann Oncol 2012; 23(9): 2265–2271

[29] Cowan M , Swetzig WM , Adorno-Cruz V , Pineda MJ , Neubauer NL , Berry E , Lurain JR , Shahabi S , Taiym D , Nelson V , O’Shea KL , Kocherginsky M , Matei D . Efficacy and safety of tivozanib in recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer, an NCCN phase II trial. Gynecol Oncol 2021; 163(1): 57–63

[30] Hirte H , Lheureux S , Fleming GF , Sugimoto A , Morgan R , Biagi J , Wang L , McGill S , Ivy SP , Oza AM . A phase 2 study of cediranib in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: a trial of the Princess Margaret, Chicago and California Phase II Consortia. Gynecol Oncol 2015; 138(1): 55–61

[31] Matulonis UA , Berlin S , Ivy P , Tyburski K , Krasner C , Zarwan C , Berkenblit A , Campos S , Horowitz N , Cannistra SA , Lee H , Lee J , Roche M , Hill M , Whalen C , Sullivan L , Tran C , Humphreys BD , Penson RT . Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol 2009; 27(33): 5601–5606

[32] Matulonis UA , Lee J , Lasonde B , Tew WP , Yehwalashet A , Matei D , Behbakht K , Grothusen J , Fleming G , Lee NK , Arnott J , Bray MR , Fletcher G , Brokx RD , Castonguay V , Mackay H , Sidor CF , Oza AM . ENMD-2076, an oral inhibitor of angiogenic and proliferation kinases, has activity in recurrent, platinum resistant ovarian cancer. Eur J Cancer 2013; 49(1): 121–131

[33] Zhang Y , Chen J , Wei W , Zheng L , Li H , Feng Y , Wan T , Qiu J , Jiang X , Xiong Y , Li J , Song L , Liu J , Huang H . Anlotinib (AL3818) plus pemetrexed in patients with recurrent platinum-resistant advanced epithelial ovarian cancer: a single-arm, open-label, phase II study. J Clin Oncol 2020; 38(15 suppl): e18078

[34] Zhang X , Jiang M , Li T , Lan H , Ning C , Wang G . Anlotinib enhanced the efficacy of pembrolizumab in refractory or recurrent High-Grade Serous Ovarian Cancer by regulating the tumor microenvironment (LBA 7). Gynecol Oncol 2023; 176: S32

[35] Miller D , Miller DS , Cheung E , Huang M , Schlumbrecht M , Garcia A , Loch M , Jernigan A , Li Z , Chen M , Chen J . Phase Ib/IIa study assessing the safety and efficacy of adding AL3818 (anlotinib) to standard platinum-based chemotherapy in subjects with recurrent or metastatic endometrial, ovarian or cervical carcinoma. Ann Oncol 2019; 30: v422

[36] Han B , Li K , Wang Q , Zhang L , Shi J , Wang Z , Cheng Y , He J , Shi Y , Zhao Y , Yu H , Zhao Y , Chen W , Luo Y , Wu L , Wang X , Pirker R , Nan K , Jin F , Dong J , Li B , Sun Y . Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: the ALTER 0303 phase 3 randomized clinical trial. JAMA Oncol 2018; 4(11): 1569–1575

[37] Sun Y , Niu W , Du F , Du C , Li S , Wang J , Li L , Wang F , Hao Y , Li C , Chi Y . Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol 2016; 9(1): 105

[38] Frenel JS , Kim JW , Aryal N , Asher R , Berton D , Vidal L , Pautier P , Ledermann JA , Penson RT , Oza AM , Korach J , Huzarski T , Pignata S , Colombo N , Park-Simon TW , Tamura K , Sonke GS , Freimund AE , Lee CK , Pujade-Lauraine E . Efficacy of subsequent chemotherapy for patients with BRCA1/2-mutated recurrent epithelial ovarian cancer progressing on olaparib versus placebo maintenance: post-hoc analyses of the SOLO2/ENGOT Ov-21 trial. Ann Oncol 2022; 33(10): 1021–1028

[39] Foote SA Jr , Liang MI , Ehrisman JA , Cohn DE , Jewell E , Havrilesky LJ . Targeted composite value-based endpoints in platinum-sensitive recurrent ovarian cancer. Gynecol Oncol 2019; 152(3): 445–451

[40] Pujade-Lauraine E , Selle F , Scambia G , Asselain B , Marmé F , Lindemann K , Colombo N , Mądry R , Glasspool R , Vergote I , Korach J , Lheureux S , Dubot C , Oaknin A , Zamagni C , Heitz F , Gladieff L , Rubio-Pérez MJ , Scollo P , Blakeley C , Shaw B , Ray-Coquard I , Redondo A; OReO/ENGOT-ov38 investigators . Maintenance olaparib rechallenge in patients with platinum-sensitive relapsed ovarian cancer previously treated with a PARP inhibitor (OReO/ENGOT-ov38): a phase IIIb trial. Ann Oncol 2023; 34(12): 1152–1164

[41] Rustin GJ , Timmers P , Nelstrop A , Shreeves G , Bentzen SM , Baron B , Piccart MJ , Bertelsen K , Stuart G , Cassidy J , Eisenhauer E . Comparison of CA-125 and standard definitions of progression of ovarian cancer in the intergroup trial of cisplatin and paclitaxel versus cisplatin and cyclophosphamide. J Clin Oncol 2006; 24(1): 45–51

RIGHTS & PERMISSIONS

Higher Education Press